Sustained release of superoxide dismutase mimics from implantable of insertable medical devices

ABSTRACT

An implantable or insertable medical device is provided which comprises (a) a superoxide dismutase mimic and (b) a polymeric release region. Upon administration to a patient, the polymeric release region controls the release of the superoxide dismutase mimic, which is beneficially selected from a metal-chelate superoxide dismutase mimic and a nitroxide superoxide dismutase mimic. Also provided is a method of making an implantable or insertable medical device.

STATEMENT OF RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/170,268 filed Jun. 11, 2002, now U.S. Pat. No. 6,835,387 entitled“Sustained Release Of Superoxide Dismutase Mimics From Implantable OrInsertable Medical Devices,” which is incorporated by reference hereinin its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to implantable or insertable medicaldevices and more particularly to implantable or insertable medicaldevices comprising a polymer that releases a therapeutic agent.

2. Brief Description of the Background Art

Superoxide dismutase mimics are enzymes that catalyze dismutation ofsuperoxide radicals (O_(2′) ⁻) by converting them to less reactivehydrogen peroxide (H₂O₂) and dioxygen (O₂). The body's response toimplanted biomedical materials typically involves inflammation tovarying degrees. To address this inflammation, superoxide dismutasemimics have been covalently attached to the surfaces of variousbiomaterials for implantation. See Udipi, K. et al, “Modification ofinflammatory response to implanted biomedical materials in vivo bysurface bound superoxide dismutase mimics,” J. Biomed Mater. Res. 2000Sep. 15; 51(4):549–60.

Local delivery of therapeutic agents from implantable or insertablemedical devices is an important new technology in the treatment ofdiseases.

For example, intraluminal stents are commonly inserted into the coronaryartery after percutaneous transluminal coronary angioplasty procedures.Such stents are provided to maintain the patency of the coronary arteryby supporting the arterial walls and preventing abrupt reclosure orcollapse thereof, which can occur after the angioplasty procedure.However, the presence of a stent can exacerbate restenosis of thevessel.

In response to this problem, local delivery of a number ofrestenosis-inhibiting therapeutic agents (such as paclitaxel, rapamycin,nitric oxide donors, and so forth) from coatings of stents that havebeen inserted after percutaneous transluminal coronary angioplastyprocedures has been proposed.

However, the technology associated with drug delivery from coatedvascular medical devices such as coronary stents is a relatively newone. Moreover, while numerous therapeutic agents have been proposed asnoted above, it is possible that certain of these agents will ultimatelybe found to act on an inappropriate cell physiology, or that they arenot be presented to the vasculature in appropriate concentrations.

SUMMARY OF THE INVENTION

In accordance with the present invention, an implantable or insertablemedical device, for example, a vascular stent, is provided whichcomprises (a) a superoxide dismutase mimic and (b) a polymeric releaseregion. Upon administration to a patient, the polymeric release regioncontrols the release of the superoxide dismutase mimic, which isbeneficially selected from a metal-chelate superoxide dismutase mimicand a nitroxide superoxide dismutase mimic.

Examples of implantable or insertable medical devices appropriate forthe practice of the present invention, besides vascular stents, includecatheters, balloons, cerebral aneurysm filler coils and arterio-venousshunts as well as non-vascular stents such as biliary stents and renalstents.

In some embodiments, the superoxide dismutase mimic is a nitroxidecompound, for example, 2,2,6,6-tetramethylpiperidine-1-yloxy,4-hydroxytetramethyl-piperidine-1-oxyl or4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-N-oxyl. In other embodiments,the superoxide dismutase mimic is a metal-chelate compound, for example,a metal-pentaazacyclopentadecane compound, a metal-porphyrin compound, ametal-porphine compound, a metal-desferioxamine compound, ametal-bis(cyclohexylpyridine) compound or a salen-metal compound.

Typically, the polymeric release region is either a polymeric matrixwithin which the superoxide dismutase mimic is disposed, or a polymericbarrier layer that is disposed over the superoxide dismutase mimic.Numerous polymers can be used in the construction of the polymericrelease region. One particularly preferred group of polymers arecopolymers of isobutylene and styrene.

The medical devices of the present invention can be administered in thetreatment of a number of diseases and conditions, including restenosis,gastrointestinal inflammation, and inflammatory processes involving thevasculature or other lumens within the body (e.g., duct inflammation).

The release profile associated with the devices of the present inventioncan be tailored to the treatment of interest. In some embodiments, therelease profile is an extended release profile in which less than 50% ofthe total amount of superoxide dismutase mimic that is released into thevasculature from the medical device is released within the first 24hours of administration.

According to further embodiments of the present invention, a method offorming an implantable or insertable medical device is provided. Themethod comprises: (a) providing a solution or dispersion comprising (i)a superoxide dismutase mimic selected from a metal-chelate superoxidedismutase mimic and a nitroxide superoxide dismutase mimic, (ii) apolymer and (iii) a solvent; (b) contacting the solution or dispersionwith a medical device; and (c) removing the solvent to form a superoxidedismutase mimic-containing polymer matrix on the medical device. Thesolution or dispersion can be contacted with the medical device in anumber of ways, including spraying the medical device with the solutionor dispersion, or dipping the medical device in the solution ordispersion.

One advantage of the present invention is that implantable or insertablemedical devices are provided, which enable the extended release ofsuperoxide dismutase mimics from the device surface.

In contrast to prior art implantable biomedical materials in whichsuperoxide dismutase mimics are covalently attached at the surface, themedical devices of the present invention are also advantageous at leastin that: (1) the superoxide dismutase mimics are released to surroundingtissue, allowing the surrounding material to be treated, and (2) theamount of superoxide dismutase mimic provided can be an order ofmagnitude greater than that provided by surface attachment techniques.

A further advantage of the present invention is that treatment methods,including a method for the treatment of restenosis, are provided, whichutilize the above medical devices.

In connection with the controlled release aspects of the devices of thepresent invention, yet another advantage is that a subject can betreated without significant risk of local overdose.

Still another advantage of the present invention is that, due to thecatalytic nature of superoxide dismutase mimics, side effects areexpected to be minimal.

These and other embodiments and advantages of the present invention willreadily become apparent to those of ordinary skill in the art uponreview of the Detailed Description and claims to follow.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with various embodiments of the invention, implantable orinsertable medical devices are provided that comprise a polymer releaseregion for a superoxide dismutase mimic. Typically, the superoxidedismutase mimic is (a) disposed within the polymer release region, inwhich case the polymer release region may be referred to herein as apolymer matrix, or (b) disposed beneath the polymer release region, inwhich case the polymer release region may be referred to herein as apolymer barrier layer. As a result of the polymer release region, atleast a portion of the superoxide dismutase mimic within the medicaldevice is released upon administering the medical device to thevasculature a patient.

Diseases and conditions that are treated using the medical devices ofthe present invention include restenosis, gastrointestinal inflammation,and inflammatory processes involving the vasculature or other lumenswithin the body (e.g., duct inflammation). As used herein, “treatment”refers the prevention of a disease or condition, the reduction orelimination of symptoms associated with a disease or condition, or thesubstantial or complete elimination a disease or condition. Preferredsubjects are vertebrate subjects, more preferably mammalian subjects andmost preferably human subjects.

Superoxide dismutase mimics are enzymes that are understood to catalyzedismutation of superoxide radicals (O_(2′) ⁻) by converting them tohydrogen peroxide (H₂O₂) and dioxygen (O₂). As a result, superoxidedismutase mimics are used in connection with the present invention toaddress the presence of overabundant superoxide associated with variousdiseases and conditions.

As one example, and without wishing to be bound by theory, superoxidedismutase mimics can be used to address the presence of overabundantsuperoxide in atherosclerotic lesions following stent implantation. Byaddressing this basic issue, it is believed that the inflammatoryresponse to the stent is suppressed and restenosis is limited. Using themedical devices of the invention, the release of the superoxidedismutase mimic can be controlled and can provide a protective effectover an extended period of time. According to one specific embodiment ofthe invention, a coronary stent, which has an overall coating weight ofabout 500 μg (of which about 150 μg is superoxide dismutase mimic) andwhich releases the superoxide dismutase mimic over a period of 2–4weeks, is implanted in the coronary artery to combat restenosis.

Superoxide dismutase mimics are preferred over the endogenous superoxidedismutase enzyme for the practice of the invention for a number ofreasons, including the fact that they are typically smaller than theendogenous superoxide dismutase enzyme and hence are better able todiffuse from the medical device and into the tissue surrounding themedical device (e.g., the media and adventitia of a coronary arteryadjacent a stent).

Superoxide dismutase mimics can be broken down into two groups:metal-dependent superoxide dismutase mimics and metal-independentsuperoxide dismutase mimics. The metal dependent superoxide dismutasemimics typically comprise a transition metal such as Mn, Cu or Fe. Themetal-independent superoxide dismutase mimics typically are nitroxidecomplexes.

Preferred metal-dependent superoxide dismutase mimics are metal-chelatecompounds and include (a) metal-pentaazacyclopentadecane superoxidedismutase mimics, including Mn[II]dichloro(1,4,7,10,13-pentaazacyclopentadecane) (MnPAM), Mn[II]dichloro(2R,3R,8R,9R-bis-cyclohexano-1,4,7,10,13-pentaazacyclopentadecane)(SC-55858), as well as other pentaazacyclopentadecanes such as thosedescribed in U.S. Pat. Nos. 6,214,817 and 5,874,421, which are herebyincorporated by reference; (b) metal-porphyrin superoxide dismutasemimics including Mn[III] tetrakis(4-benzoic acid)porphyrin (MnTBAP),Mn[III] tetrakis(1-methyl-4-pyridyl) porphyrin, (MnTMPyP), Mn[III]tetra(4-pyridyl)porphyrin, (MnTPyP), Mn[III]tetrakis(trimethylammonio)phenyl porphyrin (MnTMAP), as well as othermetal-porphyrin superoxide dismutase mimics such as those disclosed inU.S. Pat. No. 6,103,714, which is hereby incorporated by reference; (c)metal-porphine superoxide dismutase mimics including Fe[III]tetrakis(4-N-methylpyridyl)porphine (FeTMPP); (d) metal-desferioxaminesuperoxide dismutase mimics including manganese desferioxamine (Mndf);(e) Fe[II]tetrakis-N,N,N′,N′-(2-pyridylmethyl)ethylenediamine(Fe(II)TPEN); (f) metal-bis(cyclohexylpyridine) compounds, includingM40403, a manganese(II) complex with abis(cyclohexylpyridine)-substituted ligand; (g)Cu(II)-tetraanhydro-aminobenzaldehyde (TAAB); and (h) salen-metalsuperoxide dismutase mimics, including salen-Mn, salen-Co, salen-Fe,salen-V, salen-Cr and salen-Ni complexes, such those described in U.S.Pat. No. 5,696,109, which is hereby incorporated by reference.

Metal-independent superoxide dismutase mimics include nitroxidesuperoxide dismutase mimics such as2,2,6,6-tetramethylpiperidine-1-yloxy (TEMPO),4-hydroxytetramethyl-piperidine-1-oxyl (TEMPOL) and4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-N-oxyl (TPL).

Metal-chelate superoxide dismutase mimics such as those discussed aboveare particularly preferred for the practice of the present invention.

Preferred implantable or insertable medical devices for use inconjunction with the present invention include vascular and non-vascularmedical devices, including catheters, guide wires, balloons, filters(e.g., vena cava filters), stents (e.g., coronary vascular stents,cerebral stents, renal stents including urethral stents and ureteralstents, biliary stents, tracheal stents, gastrointestinal stents andesophageal stents), arterio-venous shunts, stent grafts, cerebralaneurysm filler coils (including GDC [Guglilmi detachable coils] andmetal coils), vascular grafts, myocardial plugs, patches, pacemakers andpacemaker leads and heart valves.

Medical devices made in accordance with the present invention can beplaced in a variety of bodily locations for contact with bodily tissueand/or fluid. Non-limiting examples are tumors; organs including but notlimited to the heart, various body lumens, coronary or peripheralvascular system, lungs, trachea, esophagus, brain, liver, kidney,bladder, urethra and ureters, eye, intestines, stomach, pancreas, ovary,and prostate; skeletal muscle; smooth muscle; breast; cartilage; andbone.

Depending upon the application at hand, the polymer release region canbe associated with the medical device in a number of ways. For example,the polymer release region can constitute the entirety of the medicaldevice, or it can constitute just a portion of the medical device. Theportion of the medical devices can be, for example, (a) one or moremedical device coatings, (b) one or more entire medical devicecomponents, (c) one or more portions of medical device components, andso forth.

In many preferred embodiments, a polymer release region is provided inthe form of a layer, for example, a coating on a medical device surface,including internal and/or external surfaces. The medical device surfaceor surfaces upon which the polymer release region is disposed canconstitute a wide variety of materials, including glasses, metals,polymers, ceramics and combinations thereof.

Polymer materials for use in forming the polymer release region includeessentially any polymeric material (including copolymers and polymerblends) that is compatible with the superoxide dismutase mimic, iscompatible with the medical device, allows for the release of thesuperoxide dismutase mimic, is compatible with the administration site,and so forth. The polymers may be crosslinked or uncrosslinked, linearor branched, natural or synthetic, thermoplastic or thermosetting.

Exemplary polymers include the following: polycarboxylic acid polymersand copolymers including polyacrylic acids (e.g., acrylic latexdispersions and various polyacrylic acid products such as HYDROPLUS,available from Boston Scientific Corporation, Natick Mass. and describedin U.S. Pat. No. 5,091,205, the disclosure of which is herebyincorporated herein by reference, and HYDROPASS, also available fromBoston Scientific Corporation); acetal polymers and copolymers; acrylateand methacrylate polymers and copolymers; cellulosic polymers andcopolymers, including cellulose acetates, cellulose nitrates, cellulosepropionates, cellulose acetate butyrates, cellophanes, rayons, rayontriacetates, and cellulose ethers such as carboxymethyl celluloses andhydoxyalkyl celluloses; polyoxymethylene polymers and copolymers;polyimide polymers and copolymers such as polyether block imides,polybismaleinimides, polyamidimides, polyesterimides, andpolyetherimides; polysulfone polymers and copolymers includingpolyarylsulfones and polyethersulfones; polyamide polymers andcopolymers including nylon 6,6, polycaprolactams and polyacrylamides;resins including alkyd resins, phenolic resins, urea resins, melamineresins, epoxy resins, allyl resins and epoxide resins; polycarbonates;polyacrylonitriles; polyvinylpyrrolidones (cross-linked and otherwise);anhydride polymers and copolymers including maleic anhydride polymers;polymers and copolymers of vinyl monomers including polyvinyl alcohols,polyvinyl halides such as polyvinyl chlorides, ethylene-vinylacetatecopolymers (EVA), polyvinylidene chlorides, polyvinyl ethers such aspolyvinyl methyl ethers, polystyrenes, styrene-butadiene copolymers,acrylonitrile-styrene copolymers, acrylonitrile-butadiene-styrenecopolymers, styrene-butadiene-styrene copolymers andstyrene-isobutylene-styrene copolymers, polyvinyl ketones,polyvinylcarbazoles, and polyvinyl esters such as polyvinyl acetates;polybenzimidazoles; ionomers; polyalkyl oxide polymers and copolymersincluding polyethylene oxides (PEO); glycosaminoglycans; polyestersincluding polyethylene terephthalates and aliphatic polyesters such aspolymers and copolymers of lactide (which includes lactic acid as wellas d-,l- and meso lactide), epsilon-caprolactone, glycolide (includingglycolic acid), hydroxybutyrate, hydroxyvalerate, para-dioxanone,trimethylene carbonate (and its alkyl derivatives), 1,4-dioxepan-2-one,1,5-dioxepan-2-one, and 6,6-dimethyl-1,4-dioxan-2-one (a copolymer ofpolylactic acid and polycaprolactone is one specific example); polyetherpolymers and copolymers including polyarylethers such as polyphenyleneethers, polyether ketones, polyether ether ketones; polyphenylenesulfides; polyisocyanates (e.g., U.S. Pat. No. 5,091,205 describesmedical devices coated with one or more polyisocyanates such that thedevices become instantly lubricious when exposed to body fluids);polyolefin polymers and copolymers, including polyalkylenes such aspolypropylenes, polyethylenes (low and high density, low and highmolecular weight), polybutylenes (such as polybut-1-ene andpolyisobutylene), poly-4-methyl-pen-1-enes, ethylene-alpha-olefincopolymers, ethylene-methyl methacrylate copolymers and ethylene-vinylacetate copolymers; fluorinated polymers and copolymers, includingpolytetrafluoroethylenes (PTFE),poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modifiedethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidenefluorides (PVDF); silicone polymers and copolymers; polyurethanes (e.g.,BAYHYDROL polyurethane dispersions); p-xylylene polymers;polyiminocarbonates; copoly(ether-esters) such as polyethyleneoxide-polylactic acid copolymers; polyphosphazines; polyalkyleneoxalates; polyoxaamides and polyoxaesters (including those containingamines and/or amido groups); polyorthoesters; biopolymers, such aspolypeptides, proteins, polysaccharides and fatty acids (and estersthereof), including fibrin, fibrinogen, collagen, elastin, chitosan,gelatin, starch, glycosaminoglycans such as hyaluronic acid; as well asblends and copolymers of the above.

Block copolymers having at least two polymeric blocks A and B are onepreferred group of polymers for use in connection with the presentinvention. Examples of such block copolymers include the following: (a)BA (linear diblock), (b) BAB or ABA (linear triblock), (c) B(AB)_(n) orA(BA)_(n) (linear alternating block), or (d) X-(AB)_(n) or X-(BA)_(n)(includes diblock, triblock and other radial block copolymers), where nis a positive whole number and X is a starting seed molecule.

One specific preferred group of polymers have X-(AB)_(n) structures,which are frequently referred to as diblock copolymers and triblockcopolymers where n=1 and n=2, respectively (this terminology disregardsthe presence of the starting seed molecule, for example, treating A-X-Aas a single A block with the triblock therefore denoted as BAB). Wheren=3 or more, these structures are commonly referred to as star-shapedblock copolymers.

The A blocks are preferably soft elastomeric components which are basedupon one or more polyolefins, more preferably a polyolefinic blockhaving alternating quaternary and secondary carbons of the generalformulation: —(CRR′—CH₂)_(n)—, where R and R′ are linear or branchedaliphatic groups such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl and so forth, or cyclic aliphatic groups such as cyclohexane,cyclopentane, and the like, with and without pendant groups. Polymers ofisobutylene,

(i.e., polymers where R and R′ are the same and are methyl groups) aremore preferred.

The B blocks are preferably hard thermoplastic blocks that they, whencombined with the soft A blocks, are capable of, inter alia, altering oradjusting the hardness of the resulting copolymer to achieve a desiredcombination of qualities. Preferred B blocks are polymers ofmethacrylates or polymers of vinyl aromatics. More preferred B blocksare (a) made from monomers of styrene

styrene derivatives (e.g., α-methylstyrene, ring-alkylated styrenes orring-halogenated styrenes) or mixtures of the same or are (b) made frommonomers of methylmethacrylate, ethylmethacrylate hydroxyethylmethacrylate or mixtures of the same.

Particularly preferred polymers for use in connection with the presentinvention include copolymers of polyisobutylene with polystyrene orpolymethylstyrene, more preferablypolystyrene-polyisobutylene-polystyrene triblock copolymers. Thesepolymers are described, for example, in U.S. Pat. No. 5,741,331, U.S.Pat. No. 4,946,899 and U.S. Ser. No. 09/734,639, each of which is herebyincorporated by reference in its entirety.

The polymers above can also be used in connection with further auxiliarymaterials to achieve a desired result. Such auxiliary materials includebinders, blending agents, and so forth.

Numerous techniques are available for creating polymer release regionsin the form of medical devices or portions of medical devices, includingpolymer matrices and polymer barrier layers.

For example, where the selected polymer has thermoplasticcharacteristics, a variety of standard thermoplastic processingtechniques can be used to form the polymer release region, includingcompression molding, injection molding, blow molding, spinning, vacuumforming and calendaring, as well as extrusion into sheets, fibers, rods,tubes and other cross-sectional profiles of various lengths. Using theseand other techniques, devices such as balloons, catheters, stents andportions thereof can be made from.

As a specific example, where a polymer coating is desired, the coatingcan be, for example, co-extruded along with an underlying medical deviceor portion thereof.

If the superoxide dismutase mimic is stable at processing temperatures,then it can be combined with the polymer, for example, by extrusion,prior to thermoplastic processing, producing a superoxide dismutasemimic containing polymer matrix.

Polymer release regions can also be made using solvent-based techniquesin which polymer is first dissolved in a solvent and the polymersolution is subsequently used to form the polymer release region. Thesolvent should, of course, be compatible with the polymer. Preferredsolvent-based techniques of this nature include, but are not limited to,solvent casting, spin coating, web coating, solvent spraying, dipping,coating via air suspension and mechanical suspension techniques,positive displacement coating techniques, ink jet techniques,electrostatic techniques, and combinations of these processes.

If desired, the polymer/solvent mixture can contain more than onesolvent (for example, one solvent appropriate for the polymer and adifferent solvent appropriate for the superoxide dismutase mimic).

In some solvent-based techniques, a solution comprising solvent andpolymer is applied to a substrate. The substrate can be, for example,all or a portion of a medical device to which the polymer release regionis applied as a coating.

The substrate can also be, for example, a template from which thepolymer release region is removed after solvent elimination. Suchtemplate-based techniques are particularly appropriate for formingsimple objects such as sheets, tubes, cylinders and so forth, which canbe easily removed from a template substrate.

In other techniques, for example, fiber forming techniques, the polymerrelease region is formed without the aid of a substrate.

Where appropriate, techniques such as those listed above can be repeatedor combined to build up a polymer release region to a desired thickness.Polymer release region thickness can be varied in other ways as well.For example, in solvent spraying, coating thickness can be increased bymodification of coating process parameters, including increasing flowrate, slowing the movement between the device or template to be coatedand the spray nozzle, providing repeated passes and so forth.

When forming polymer matrices using solvent-based techniques, and wherethe solvent is compatible with the superoxide dismutase mimic, thesuperoxide dismutase mimic can be provided in the polymer/solventmixture, for example, in dissolved form or as a particulate suspension.Such techniques allow the superoxide dismutase mimic to be providedconcurrently with component formation. Otherwise, the superoxidedismutase mimic can be added subsequent to polymer matrix formation asdiscussed below.

After forming the polymeric release region using solvent-basedtechniques, it is preferably dried to remove the solvents. In the caseof a coating, the coating typically conforms to the underlying surfaceduring the drying process.

In some embodiments, the superoxide dismutase mimic is provided withinthe polymer matrix subsequent to its formation. For example, thesuperoxide dismutase mimic can be dissolved in a solvent that iscompatible with both the polymer and the superoxide dismutase mimic.Preferably, the polymer matrix is at most only slightly soluble in thesolvent. Subsequently, the solution is contacted with the polymer matrixsuch that the superoxide dismutase mimic is provided within the polymermatrix (e.g., by leaching/diffusion into the polymer). For this purpose,the polymer matrix can be immersed or dipped into the solution, forexample. Alternatively, the solution can be applied to polymer matrix,for example, by spraying. The polymer matrix can subsequently be dried,with the superoxide dismutase mimic remaining therein.

Regardless of the fashion by which the superoxide dismutase mimic isincorporated into the polymer matrix, a wide variety of superoxidedismutase mimic loadings are possible, with the amount of loading beingreadily determined by those of ordinary skill in the art, depending uponthe release profile that is desired. The superoxide dismutase mimiccontaining polymeric matrix can will frequently comprise from 1% or lessto 70 wt % or more superoxide dismutase mimic, with ranges of 1–2 wt %,2–4 wt %, 4–8 wt %, 16–32 wt %, 32–68 wt %, among others being possible.

In some embodiments, the polymer release region is a polymer barrierlayer. In these embodiments, the superoxide dismutase mimic is providedin a superoxide dismutase mimic containing layer below the polymerbarrier layer and diffuses through the barrier to effect release. Forexample, the superoxide dismutase mimic-containing layer can be aprecipitated layer of the superoxide dismutase mimic compound, or it canbe provided in a polymeric layer, beneath the polymer barrier layer.

In accordance with the present invention, superoxide dismutase mimic isreleased via the polymer release region to a bodily tissue or bodilyfluid upon contacting the same. The desired release profile is readilydetermined by those of ordinary skill in the art and ultimately dependsupon the condition to be treated, the nature of the superoxide dismutasemimic itself, and so forth.

An extended release profile is preferred in many instances. By “extendedrelease profile ” is meant a release profile in which less than 50% ofthe total release from the medical device that occurs over the course ofimplantation/insertion in the body occurs within the first 24 hours ofadministration. Conversely, this means that more than 50% of the totalrelease from the medical device will occur after the device has beenimplanted/inserted for 24 hours. Various extended release profiles canbe provided in accordance with the present invention including: (a) the50% release point occurring at a time that is between 24 and 48 hoursafter implantation/insertion, (b) the 50% release point occurring at atime that is between 48 and 96 hours after implantation/insertion, (c)the 50% release point occurring at a time that is between 96 and 168hours (1 week) after implantation/insertion, (d) the 50% release pointoccurring at a time that is between 1 and 2 weeks afterimplantation/insertion, (e) the 50% release point occurring at a timethat is between 2 and 4 weeks after implantation/insertion, (f) the 50%release point occurring at a time that is between 4 and 8 weeks afterimplantation/insertion, (g) the 50% release point occurring at a timethat is between 8 and 16 weeks after implantation/insertion, and (h) the50% release point occurring at a time that is between 16 and 32 weeksafter implantation/insertion.

The release rate of superoxide dismutase mimic can be varied in a numberof ways. Examples include: (a) varying the type of polymer within therelease region, (b) varying the molecular weight of the polymers withinthe release region, (c) where a copolymer or polymer blend is usedwithin the release region, varying the specific constituents of thecopolymer or polymer blend, as well as the relative amounts of theseconstituents, (d) where solvent-based techniques are used to form therelease region, varying the type and relative amounts of solvents usedin processing the polymer release region, (e) varying the porosity ofthe polymers within the release region, and (f) providing an additionalpolymer layer over the release region to further retard diffusion.

The invention is further described with reference to the followingnon-limiting Example.

EXAMPLE

Stainless steel coronary stents are coated with a polymeric matrixcontaining a superoxide dismutase mimic of choice. The polymer matrix isa polystyrene-polyisobutylene-polystyrene triblock copolymer matrix,described, for example, in U.S. Pat. No. 5,741,331, U.S. Pat. No.4,946,899 and U.S. Ser. No. 09/734,639, the disclosures of which arehereby incorporated by reference. The superoxide dismutase mimic isuniformly dispersed throughout the polymer. The coating is applied froma solution containing 1 wt % solids (SOD mimic and polymer), 74.3 wt %methylene chloride and 24.7 wt % toluene, by spray coating (or dipcoating). The coating contains from 5–30% superoxide dismutase mimic byweight. Following coating of the device, the devices are dried in avacuum oven at 40° C. for 1 hr. Extended release can be demonstrated byincubation of each coated stent in phosphate buffered saline (PBS) at37° C. An extended release profile is desirable for coronary stents,because the restenotic process occurs over several weeks following stentimplantation.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

1. An implantable or insertable medical device comprising: a superoxide dismutase mimic selected from a metal-chelate superoxide dismutase mimic and a nitroxide superoxide dismutase mimic; and a polymeric release region tat controls the release of said superoxide dismutase mimic upon administration to a patient; wherein the superoxide dismutase mimic is disposed within a polymeric matrix comprising a copolymer comprising an isobutylene monomer and a styrene monomer; and wherein the medical device is selected from a stent, a catheter, a balloon, a cerebral aneurysm filter coil, an arterio-venous shunt, a guide wire, a vena cava filter, a stent graft, a vascular graft, a myocardial plug, a patch, a pacemaker, a pacemaker lead, and a heart valve.
 2. The implantable or insertable medical device of claim 1, wherein said stent is a vascular stent.
 3. The implantable or insertable medical device of claim 1, wherein said medical device is a vascular medical device.
 4. The implantable or insertable medical device of claim 1, wherein said superoxide dismutase mimic is a nitroxide compound.
 5. The implantable or insertable medical device of claim 1, wherein said superoxide dismutase mimic is a nitroxide compound selected from 2,2,6,6-tetramethylpiperidine-1-yloxy, 4-hydroxytetramethyl-piperidine-1-oxyl and 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-N-oxyl.
 6. The implantable or insertable medical device of claim 1, wherein said superoxide dismutase mimic is a metal-chelate compound.
 7. The implantable or insertable medical device of claim 1, wherein said superoxide dismutase mimic is a metal-chelate compound selected from metal-pentaazacyclopentadecane compounds, metal-porphine compounds, metal-porphine compounds, metal-desferioxamine compounds, metal-bis(cyclohexylpyridine) compounds and salen-metal compounds.
 8. A method for treating a disease or condition of the vasculature comprising implanting or inserting the medical device of claim 1 into the body of a patient.
 9. A method for treating a disease or condition of the vasculature comprising implanting or inserting the medical device of claim 1 into the vasculature of a patient.
 10. The method of claim 8, wherein 50% of the total amount of superoxide dismutase mimic that is released into the body from said medical device is released beyond 24 hours after administration.
 11. The method of claim 9, wherein said disease or condition is restenosis.
 12. A method of forming the implantable or insertable medical device of claim 1 comprising: comprising said superoxide dismutase mimic, said copolymer and a solvent; contacting said solution or dispersion with a medical device; and removing said solvent to form a superoxide dismutase mimic-containing polymeric matrix on said medical device, wherein said polymeric matrix controls the release of said superoxide dismutase mimic upon administration to a patient.
 13. The method of claim 12, wherein said superoxide dismutase mimic is a nitroxide compound.
 14. The method of claim 12, wherein said superoxide dismutase mimic is a nitroxide compound selected from 2,2,6,6-tetramethylpiperidine-1-yloxy, 4-hydroxytetramethyl-piperidine-1-oxyl and 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-N-oxyl.
 15. The method of claim 12, wherein said superoxide dismutase mimic is a metal-chelate compound.
 16. The method of claim 12, wherein said superoxide dismutase mimic is selected from metal-pentaazacyclopentadecane compounds, metal-porphine compounds, metal-porphine compounds, metal-desferioxamine compounds, metal-bis(cyclohexylpyridine) compounds and salen-metal compounds.
 17. The method of claim 12, wherein said solution or dispersion is contacted with said medical device by spraying said medical device with said solution or dispersion.
 18. The method of claim 12, wherein said solution or dispersion is contacted with said medical device by dipping said medical device in said solution or dispersion. 